Happy for my former mentor Howard Chang, congratulations Howard!:
www.amgen.com/newsroom/pre...

Both long-term iberdomide (7-day) and acute (6-hour) iberdomide treatment induced the strongest differential TF binding at IKZF1/ETS1 motifs. This suggests direct competition between IKAROS and ETS1 at enhancers of immune genes (7/8).

We used the new computational tool PRINT developed by our lab to investigate TF binding during exhaustion and iberdomide treatment. We find that iberdomide prevents IKAROS-mediated loss of chromatin accessibility and ejection of activating TFs at immune genes such as IFNG and IL2 (6/8).

Cereblon E3 Ligase Modulatory Drugs (CELMoDs) that degrade IKAROS are in clinical trials for multiple myeloma. Co-culturing the CELMoD iberdomide with effector T cells during chronic stimulation preserved tumor killing and cytokine secretion even after 14 days (5/8).

We leveraged our new in vitro assay to uncover epigenetic drivers of T cell exhaustion. First, we performed a CRISPR screen and nominated IKAROS (IKZF1), among other known hits, as responsible for downregulating cytokine secretion during chronic stimulation (4/8).

We use SHARE-seq, a single-cell RNA and ATAC sequencing method, and determine that these in vitro T cells exhausted after 14 days of viral stimulation resemble T cells directly sequenced from tumors in cancer patients (pubmed.ncbi.nlm.nih.gov/34914499) (3/8).

7 days of viral stimulation creates a pool of effector T cells expanded from the original donor memory T cells. However, chronic stimulation for 14 days leads to loss of tumor cell killing ability and cytokine secretion, hallmark signs of T cell exhaustion (2/8).

We develop a new in vitro model expanding human memory T cells from donor blood using endemic viruses. Our antigen-specific stimulation in the milieu of donor immune cells better captures in vivo T cell activation compared to common CD3/CD28-based activation methods (1/8).